ELEVATION OF INTRACELLULAR CYCLIC ADENOSINE-MONOPHOSPHATE INHIBITS THE EPIDERMAL GROWTH-FACTOR SIGNAL-TRANSDUCTION PATHWAY AND CELLULAR GROWTH IN PANCREATIC ADENOCARCINOMA CELL-LINES
Md. Lieberman et al., ELEVATION OF INTRACELLULAR CYCLIC ADENOSINE-MONOPHOSPHATE INHIBITS THE EPIDERMAL GROWTH-FACTOR SIGNAL-TRANSDUCTION PATHWAY AND CELLULAR GROWTH IN PANCREATIC ADENOCARCINOMA CELL-LINES, Surgery, 120(2), 1996, pp. 354-359
Background. The epidermal growth factor (EGF) signal transduction path
way, frequently activated in pancreatic cancer, is an important regula
tor of cellular growth and transformation. This study examined whether
activation of the cyclic adenosine monophosphate protein kinase ii pa
thway may inhibit the EGF signal transduction pathway in pancreatic ca
ncer cell lines. Methods. Human pancreatic cancer lines BxPC-3 and AsP
C-1 were stimulated with EGF, forskolin, or both. Forskolin is a compo
und that increases cyclic adenosine monophosphate levels. Assays of ce
ll lines were then obtained for cellular growth (MTT assay), anchorage
-independent growth (soft agar), and EGF-induced mitogen-activated pro
tein kinase activation as measured by an in-gel kinase assay. Results,
Treatment with forskolin resulted in inhibition of EGF-induced activa
tion of mitogen-activated protein kinase activity (BxPC-3 78% inhibiti
on and AsPC-1 70% inhibition, p < 0.005), diminished cellular prolifer
ation (BxPC-3 92% inhibition and AsPC-1 86% inhibition, p < 0.001), an
d formation of colonies in soft agar (BxPC-3 98% inhibition and AsPC-1
76% inhibition, p < 0.001). Forskolin did not inhibit EGF receptor au
tophosphorylation or tyrosine kinase signaling in response to EGF. Con
clusions. Forskolin-induced inhibition of mitogen-activated protein ki
nase is associated with diminished pancreatic cancer cell proliferatio
n in vitro. Use of strategies to increase cyclic adenosine monophospha
te levels may have therapeutic application in pancreatic cancer.